REDUCTIONS AND REDUCING AGENTS 1 Reductions and Reducing Agents • Basic definition of reduction: Addition of hydrogen or removal of oxygen • Addition of electrons 9:45 AM 2 Reducible Functional Groups 9:45 AM 3 Categories of Common Reducing Agents 9:45 AM 4 Relative Reactivity of Nucleophiles at the Reducible Functional Groups In the absence of any secondary interactions, the carbonyl compounds exhibit the following order of reactivity at the carbonyl This order may however be reversed in the presence of unique secondary interactions inherent in the molecule; interactions that may 9:45 AM be activated by some property of the reacting partner 5 Common Reducing Agents (Borohydrides) Reduction of Amides to Amines 9:45 AM 6 Common Reducing Agents (Borohydrides) Reduction of Carboxylic Acids to Primary Alcohols O 3 R CO2H + BH3 R O B + 3 H 3 2 Acyloxyborane 9:45 AM 7 Common Reducing Agents (Sodium Borohydride) The reductions with NaBH4 are commonly carried out in EtOH (Serving as a protic solvent) Note that nucleophilic attack occurs from the least hindered face of the 8 carbonyl Common Reducing Agents (Lithium Borohydride) The reductions with LiBH4 are commonly carried out in THF or ether Note that nucleophilic attack occurs from the least hindered face of the 9:45 AM 9 carbonyl. Common Reducing Agents (Borohydrides) The Influence of Metal Cations on Reactivity As a result of the differences in reactivity between sodium borohydride and lithium borohydride, chemoselectivity of reduction can be achieved by a judicious choice of reducing agent. 9:45 AM 10 Common Reducing Agents (Sodium Cyanoborohydride) 9:45 AM 11 Common Reducing Agents (Reductive Amination with Sodium Cyanoborohydride) 9:45 AM 12 Lithium Aluminium Hydride Lithium aluminiumhydride reacts the same way as lithium borohydride. It is however a much more reactive reducing agent than lithium borohydride. It is the strongest of the hydride reducing agents. Note that the Al-H bond is more polarized than B-H bond. Consequently the hydride in Al-H has greater hydride character and therefore more nucleophilic than the hydride in B-H. Note that unlike Na+, Li+ is a Lewis acid that co-ordinates better to the carbonyl oxygen, activating the carbonyl to nucleophilic attack. It reduces both aldehydes and ketones to alcohols 13 9:45 AM Common Reducing Agents (Lithium Aluminium Hydride) Carboxylic acids and esters are reduced by LiAlH4 to primary alcohols Note that nucleophilic hydride attacks from the least hindered face 14 Common Reducing Agents (Lithium Aluminium Hydride) Reduction of Amides and Nitriles to Amines Amides and nitriles are reduced by LiAlH4 to amines. 9:45 AM 15 Common Reducing Agents (Diisobutylaluminiumhydride) Reduction of Aldehydes and Ketones to Alcohols DIBAL-H has a tendency of effecting chelation controlled reductions 16 Common Reducing Agents (Diisobutylaluminiumhydride) Reduction of Esters to Alcohols Reduction of esters with atleast 2 equivalents of DIBAL-H provides 17 alcohols. Common Reducing Agents (Diisobutylaluminiumhydride) Partial Reduction of Esters to Aldehydes Half reduction of esters to aldehydes can be accomplished with 1 equivalent of DIBAL-H. 18 Common Reducing Agents (Diisobutylaluminiumhydride) Partial Reduction of Nitriles to Aldehydes Half reduction of a nitrile with 1 equiv of DIBAL-H followed by hydrolysis provides an aldehyde. 19 Common Hydride Reducing Agents A Comparative Analysis among the Reducing Agents 9:45 AM 20 Reductive Deoxygenation (Wolff-Kishner Reduction) Reductive Deoxygenation of Aldehydes and Ketones to Hydrocarbons High temperatures are required to effect the reduction The Basic media may however be incompatible with other functional groups Example 9:45 AM 21 Non-Metal Reducing Agents (Wolff-Kishner Reduction) Mechanism of Wolff-Kishner Reduction Reaction begins with initial formation of a hydrazone 9:45 AM 22 Common Reducing Agents (Catalytic Hydrogenation) Reduction of Alkynes and Alkenes to Alkanes Alkynes and alkenes readily undergo complete hydrogenation on metal catalysts, commonly palladium and nickel, provide alkanes. 23 Common Reducing Agents (Catalytic Hydrogenation) Reduction of Alkynes and Alkenes to Alkanes Example Ph Ph H H2 H C C Ph C C Ph Pd/C Me Me Me Me Z-Isomer Meso Ph Me H H2 H C C Ph C C Me Me Ph Pd/C Me Ph E-Isomer (+-) The stereospecific reduction of E and Z-isomers of an alkene shows that the addition of hydrogen occurs in a syn fashion. This is an indication that a highly organized transition state is involved. 24 Common Reducing Agents (Catalytic Hydrogenation) Mechanism of Reduction of Alkenes to Alkanes 9:45 AM 25 Common Reducing Agents (Catalytic Hydrogenation) Partial Reduction of Alkynes to (Z)-Alkenes Since alkynes are more reactive to catalytic hydrogenation than alkenes, controlled reduction of alkynes to alkenes without over- reduction is possible by employing a poisoned palladium catalyst (Lindlars catalyst) to deter the reduction of the intermediate alkene to a saturated alkane. Example Lindlars catalyst consists of palladium on a calcium carbonate support poisoned with lead acetate and a small amount of quinoline. 26 Common Reducing Agents (Catalytic Hydrogenation) Mechanism of the Partial Reduction of Alkynes to (Z)-Alkenes 9:45 AM 27 Common Reducing Agents (Catalytic Hydrogenation) Synthetic Applications of Partial Reduction of Alkynes to Alkenes The synthesis of Muscalure ((Z)-9-tricosene), the sex pheromone of the female housefly Musca domestica, was accomplished through a stereospecific partial reduction of an appropriate alkyne. 9:45 AM 28 Common Reducing Agents (Dissolving Metal Reduction) Stereospecific Partial Reduction of Alkynes to (E)-Alkenes The reduction of alkynes under dissolving-metal conditions occurs through radical anion intermediates initiated by successive electron and proton-transfer processes. Solutions of group 1 metals (Na or Li or K) in ammonia are used as the reducing mixture. Bright blue electron-rich solutions are obtained. Example 9:45 AM 29 Common Reducing Agents (Dissolving Metal Reduction) Mechanism of Stereospecific Partial Reduction of Alkynes to (E)- Alkenes 9:45 AM 30 Common Reducing Agents (Catalytic Hydrogenation) Synthetic Applications of Partial Reduction of Alkynes to Alkenes with Dissolving Metal Systems The biologically inactive stereoisomer (E-9-tricosene) of Muscalure (Z- 9-tricosene),the sex pheromone of the female housefly Musca domestica, can be accessed through a stereospecific partial reduction 9:45 AM of an appropriate alkyne using dissolving-metal conditions. 31 Common Reducing Agents (Dissolving Metal Reduction) Reduction of Electron Deficient Alkenes Recall a,b-unsaturated carbonyl aldehydes and ketones can be cleanly reduced to the enolate of the corresponding saturated aldehyde or ketone with lithium or sodium in liquid ammonia at low temperature. Usually one equivalent of an alcohol or NH4Cl is added to the reaction medium at the end to serve as a proton source / donor to the enolate. Example 9:45 AM 32 Common Reducing Agents (Dissolving Metal Reduction) Mechanism of Reduction of Electron Deficient Alkenes Regiospecific generation of enolates can be achieved 9:45 AM 33 Common Reducing Agents (Dissolving Metal Reduction) Synthetic Applications of Reduction of Electron Deficient Alkenes Alkylation of the regiospecifically generated enolate can be exploited. 9:45 AM 34 Common Reducing Agents (Catalytic Hydrogenation vs Dissolving Metal Reduction) Stereochemical Consequences of Catalytic Hydrogenation vs Dissolving Metal Reduction With judicious choice of reducing conditions either trans or cis fused 9:45 AM decaline systems can be accessed. 35 Partial Reduction of Aromatic π-Systems (Birch Reduction) Dissolving Metal Reduction of Aromatic systems Dissolving-metal systems are synthetically useful for the partial reduction of aromatic rings. The reaction is called Birch reduction. Electrons are the reducing agent and these come from the group 1 metals sodium, lithium or potassium in liquid ammonia. H H Na/ NH3 t-BuOH -33 oC H H e- H O-t-Bu H H H H H O-t-Bu e- 9:45 AM 36 Partial Reduction of Aromatic π-Systems (Birch Reduction) Regiochemistry of Reduction in Substituted Aromatic systems EDG EDG EDG EDG 1 OCH3 6 1 6 2 1 2 6 2 3 5 3 * 5 5 3 * 4 4 4 EDG= Electron donating group In systems with EDG: C-1, C-2, C-4 and C-6 are electron rich, consequently C-3 and C-5 are electron deficient) EWG EWG EWG EWG CO2H 6 6 1 2 * 6 1 2 1 2 * * 3 3 5 3 5 5 4 4 * 4 EWG = Electron withdrawing group In systems with EWG: C-1, C-2, C-4 and C-6 are electron deficient, consequently C-3 and C-5 are 9:45 AM electron rich) 37 Partial Reduction of Aromatic π-Systems (Birch Reduction) Mechanism of Reduction in Electron-Donating Substituted Aromatic systems 9:45 AM 38 Partial Reduction of Aromatic π-Systems (Birch Reduction) Mechanism of Reduction in Electron-Withdrawing Substituted Aromatic systems. O O C O O O O C C O O C H CO2 H CO2 1 e- Fast - 2 t-BuOH e Na/ NH 3 Na/ NH3 Excessive repulsion Radical anion stabilzed by resonance to e- of electrons in radical anion carbonyl group t-BuOH O O O O O O O O C C C C H CO2 - Fast t-BuOH e t-BuOH Na/ NH3 H H H H H H Excessive repulsion Most reactive of electrons in radical primary radical anion 1,4-Dihydro diene anion O O C 9:45 AM 39 Partial Reduction of Aromatic π-Systems (Birch Reduction) Examples OCH 3 OCH3 O O Li / NH3 H H EtOH H2O H2O OCH3 O OCH3 Na / NH 3 H t-BuOH H2O OCH3 O OCH3 Electron-donating groups are conjugated to alkene units 9:45 AM 40 Partial Reduction of Aromatic π-Systems (Birch Reduction) Examples O O C O O Na / NH3 C t-BuOH -33 oC CH 3 CH3 O N O N CH3 Li / NH3 CH3 EtOH 9:45 AM 41.